National Academy of Sciences, Proceedings of the National Academy of Sciences, 28(115), p. 7326-7331, 2018
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Significance Antibiotics generally target one of five essential cellular functions in bacteria, but many of these targets are now compromised through rapidly spreading antibiotic resistance. Bedaquiline (BDQ), a new FDA-approved antitubercular drug, targets energy metabolism: defining cellular energetics as a new target space for antibiotics. This is a relatively unexplored area, as BDQ was only FDA approved in 2012. Several studies have recently found that BDQ stimulates mycobacterial respiration, in addition to inhibiting its molecular target, the F 1 F o -ATP synthase. We show that BDQ is an ionophore, which shuttles H + and K + ions across membranes, and propose that this activity may contribute to killing of mycobacteria by BDQ. Combining ionophoric activity with high-affinity membrane protein inhibition may enhance the specificity and potency of antibiotics.